Insulin-dependent diabetes mellitus (IDDM) is a multigenenic autoimmune disease. The reasons why autoreactive T cells become activated and mediate destruction of insulin-producing beta cells are not fully understood, but an insight may be gained from one of the best animal models for IDDM - the non-obese diabetic (NOD) mouse. In both humans and NOD mice, several genes, including MHC genes, are important in the disease process. This lab has previously identified a novel diabetes susceptibility gene, Idd11, on mouse chromosome 4. The major goal of this project is to characterize IDDM susceptibility genes that may play a role in the genetics of both human and mouse disease pathogenesis. The main approach will involve the genetic and immunological characterization of Idd11 using NOD congenic mice, which have been developed in the host laboratory by replacing different NOD chromosome 4 intervals with that from a diabetes-resistant strain. The second approach is to examine linkage between IDDM and human chromosome 1, which shares syntenic homology with mouse chromosome 4. Preliminary genetic analysis of affected siblings from 208 Australian and British families for chromosome 1 provided evidence for at least two novel susceptibility genes. The specific questions to be investigated are: 1) Does chromosome 1 show linkage to IDDM in American families? 2) What are the smallest definable chromosomal regions that contain these susceptibility genes? 3) What role in the disease process does Idd11 play? 4) Which actual genes on mouse chromosome 4 and human chromosome 1 are diabetes susceptibility genes? Answering these questions may provide a screening test for at-risk individuals as well as offering prospects for disease prevention.